Compounds which have the property of inhibiting the action of metalloproteinases involved in connective tissue breakdown such as collagenase, stromelysin and gelatinase (known as "matrix metalloproteinases", and herein referred to as MMPs) are thought to be potentially useful for the treatment or prophylaxis of conditions involving such tissue breakdown, for example rheumatoid arthritis, osteoarthritis, osteopenias such as osteoporosis, periodontitis, gingivitis, corneal epidermal or gastric ulceration, and tumour metastasis, invasion and growth. MMP inhibitors are also of potential value in the treatment of neuroinflammatory disorders, including those involving myelin degradation, for example multiple sclerosis, as well as in the management of angiogenesis dependent diseases, which include arthritic conditions and solid tumour growth as well as psoriasis, proliferative retinopathies, neovascular glaucoma, ocular tumours, angiofibromas and hemangiomas. However, the relative contributions of individual MMPs in any of the above disease states is not yet fully understood.
Metalloproteinases are characterised by the presence in the structure of a zinc (II) ionic site. It is now known that there exists a range of metalloproteinase enzymes that includes fibroblast collagenase (Type 1), PMN-collagenase, 72 kDa-gelatinase, 92 kDa-gelatinase, stromelysin, stromelysin-2 and PUMP-1 (J. F. Woessner, FASEB J, 1991, 5, 2145-2154). Many known MMP inhibitors are peptide derivatives, based on naturally occuring amino acids, and are analogues of the cleavage site in the collagen molecule. A recent paper by Chapman et. al. (J. Med. Chem. 1993, 36, 4293-4301) reports some general structure/activity findings in a series of N-carboxyalkyl peptides. Other known MMP inhibitors are less peptidic in structure, and may more properly be viewed as pseudopeptides or peptide mimetics. Such compounds usually have a functional group capable of binding to the zinc (II) site in the MMP, and known classes include those in which the zinc binding group is a hydroxamic acid, carboxylic acid, sulphydryl, and oxygenated phosphorus (eg phosphinic acid and phosphonamidate including aminophosphonic acid) groups.
Two known classes of pseudopeptide or peptide mimetic MMP inhibitors have a hydroxamic acid group and a carboxylic group respectively as their zinc binding groups. With a few exceptions, such known MMPs may be represented by the structural formula (I) ##STR1## in which X is the zinc binding hydroxamic acid (--CONHOH) or carboxylic acid (--COOH) group and the groups R.sub.1 to R.sub.5 are variable in accordance with the specific prior art disclosures of such compounds. Examples of patent publications disclosing such structures are given below.
In such compounds, it is generally understood in the art that variation of the zinc binding group and the substituents R.sub.1, R.sub.2 and R.sub.3 can have an appreciable effect on the relative inhibition of the metalloproteinase enzymes. The group X is thought to interact with metalloproteinase enzymes by binding to a zinc (II) ion in the active site. Generally the hydroxamic acid group is preferred over the carboxylic acid group in terms of inhibitory activity against the various metalloproteinase enzymes. However, the carboxylic acid group in combination with other substituents can provide selective inhibition of gelatinase (EP489,577-A). The R.sub.1, R.sub.2 and R.sub.3 groups are believed to occupy respectively the P1, P1' and P2' amino acid side chain binding sites for the natural enzyme substrate. There is evidence that a larger R.sub.1 substituent can enhance activity against stromelysin, and that a (C.sub.1 -C.sub.6)alkyl group (such as iso-butyl) at R.sub.2 may be preferred for activity against collagenase whilst a phenylalkyl group (such as phenylpropyl) at R.sub.2 may provide selectivity for gelatinase over the other metalloproteinases.
Tumour necrosis factor (herein referred to as "TNF") is a cytokine which is produced initially as a cell-associated 28 kD precursor. It is released as an active, 17 kD form, which can mediate a large number of deleterious effects in vivo. When administered to animals or humans it causes inflammation, fever, cardiovascular effects, haemorrhage, coagulation and acute phase responses, similar to those seen during acute infections and shock states. Chronic administration can also cause cachexia and anorexia. Accumulation of excessive TNF can be lethal.
There is considerable evidence from animal model studies that blocking the effects of TNF with specific antibodies can be beneficial in acute infections, shock states, graft versus host reactions and autoimmune disease. TNF is also an autocrine growth factor for some myelomas and lymphomas and can act to inhibit normal haematopoiesis in patients with these tumours.
Compounds which inhibit the production or action of TNF are therefore thought to be potentially useful for the treatment or prophylaxis of many inflammatory, infectious, immunological or malignant diseases. These include, but are not restricted to, septic shock, haemodynamic shock and sepsis syndrome, post ischaemic reperfusion injury, malaria, Crohn's disease, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic disease, cachexia, graft rejection, cancer, autoimmune disease, rheumatoid arthritis, multiple sclerosis, radiation damage, toxicity following administration of immunosuppressive monoclonal antibodies such as OKT3 or CAMPATH-1 and hyperoxic alveolar injury. Since excessive TNF production has been noted in several diseases or conditions also characterised by MMP-mediated tissue degradation, compounds which inhibit both MMPs and TNF production may have particular advantages in the treatment or prophylaxis of diseases or conditions in which both mechanisms are involved.
Recently, WO 93/20047 disclosed a class of hydroxamic acid based MMP inhibitors which also are active in inhibiting TNF production.
As mentioned above, MMP inhibitors have been proposed with hydroxamic acid or carboxylic acid zinc binding groups. The following patent publications disclose hydroxamic acid-based MMP inhibitors:
U.S. Pat. No. 4,599,361 (Searle) PA0 EP-A-0236872 (Roche) PA0 EP-A-0274453 (Bellon) PA0 WO 90/05716 (British Bio-technology) PA0 WO 90/05719 (British Bio-technology) PA0 WO 91/02716 (British Bio-technology) PA0 EP-A-0489577 (Celltech) PA0 EP-A-0489579 (Celltech) PA0 EP-A-0497192 (Roche) PA0 WO 92/13831 (British Bio-technology) PA0 WO 92/17460 (SmithKline Beecham) PA0 WO 92/22523 (Research Corporation Technologies) PA0 WO 93/09090 (Yamanouchi) PA0 WO 93/09097 (Sankyo) PA0 WO 93/20047 (British Bio-technology) PA0 WO 93/24449 (Celltech) PA0 WO 93/24475 (Celltech) PA0 EP-A-0574758 (Roche) PA0 EP-A-0489577 (Celltech) PA0 EP-A-0489579 (Celltech) PA0 WO 93/24449 (Celltech) PA0 WO 93/24475 (Celltech) PA0 X is a --CO.sub.2 H or --CONHOH group; PA0 R.sub.1 is hydrogen; (C.sub.1 -C.sub.6)alkyl; (C.sub.2 -C.sub.6)alkenyl; phenyl; substituted phenyl; phenyl (C.sub.1 -C.sub.6)alkyl); substituted phenyl(C.sub.1 -C.sub.6)alkyl; heterocyclyl; substituted heterocyclyl; heterocyclyl(C.sub.1 -C.sub.6)alkyl; substituted heterocyclyl(C.sub.1 -C.sub.6)alkyl; a group BSO.sub.n A- wherein n is 0, 1 or 2 and B is hydrogen or a (C.sub.1 -C.sub.6) alkyl, phenyl, substituted phenyl, heterocyclyl, (C.sub.1 -C.sub.6)acyl, phenacyl or substituted phenacyl group, and A represents (C.sub.1 -C.sub.6)alkyl; amino; protected amino; acylamino; OH; SH; (C.sub.1 -C.sub.6)alkoxy; (C.sub.1 -C6)alkylamino; di-(C.sub.1 -C.sub.6)alkylamino; (C.sub.1 -C.sub.6)alkylthio; aryl (C.sub.1 -C.sub.6)alkyl; amino(C.sub.1 -C.sub.6)alkyl; hydroxy(C.sub.1 -C.sub.6)alkyl, mercapto(C.sub.1 -C.sub.6)alkyl or carboxy(C.sub.1 -C.sub.6)alkyl wherein the amino-, hydroxy-, mercapto- or carboxyl-group are optionally protected or the carboxyl- group amidated; lower alkyl substituted by carbamoyl, mono(lower alkyl)carbamoyl, di(lower alkyl)carbamoyl, di(lower alkyl)amino, or carboxy-lower alkanoylamino; PA0 R.sub.2 is a (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6)alkynyl, phenyl(C.sub.1 -C.sub.6)alkyl, heteroaryl(C.sub.1 -C.sub.6)alkyl, cycloalkyl(C.sub.1 -C.sub.6)alkyl or cycloalkenyl(C.sub.1 -C.sub.6) alkyl group, any one of which may be optionally substituted by one or more substituents selected from (C.sub.1 -C.sub.6)alkyl, --O(C.sub.1 -C.sub.6)alkyl, --S(C.sub.1 -C.sub.6)alkyl, halo and cyano (--CN); PA0 R.sub.3 is the characterising group of a natural or non-natural .alpha. amino acid in which any functional groups may be protected; PA0 R.sub.4 is a phenyl or 5- or 6-membered heteroaryl ring wherein any ring nitrogen atom may be oxidised as an N-oxide, which may be optionally fused to a benzene ring or to a 5-, 6- or 7-membered heterocyclic ring, and wherein any of the rings may be optionally substituted by: PA0 R.sub.5 is hydrogen or a (C.sub.1 -C.sub.6)alkyl group; PA0 R.sub.3 may also be a group --CR.sub.a R.sub.b R.sub.c in which: PA0 More specifically with respect to the groups R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 in compounds of the invention: PA0 3R-(2,2-Dimethyl-1S-pyridin-2-ylcarbamoyl-propylcarbamoyl)-5-methyl-2S-prop en-2-yl-hexanohydroxamic acid, PA0 3R-(2,2-Dimethyl-1S-pyridin-2-ylcarbamoyl-propylcarbamoyl)-2S-hydroxy-5-met hylhexanohydroxamic acid, PA0 3R-(2,2-Dimethyl-1S-(5-methylthiadiazol-2-ylcarbamoyl)-propylcarbamoyl)-2S- hydroxy-5-methylhexanohydroxamic acid, PA0 3R-(2,2-Dimethyl-1S-(3-methoxyphenyl)carbamoyl-propylcarbamoyl)-2S-hydroxy- 5-methylhexanohydroxamic acid, PA0 3R-(2,2-Dimethyl-1S-pyrid-3-ylcarbamoyl-propylcarbamoyl)-2S-hydroxy-5-methy lhexanohydroxamic acid and PA0 3R-(2,2-Dimethyl-1S-pyridin-2-ylcarbamoyl-propylcarbamoyl)-5-methyl-2S-phth alimidomethylhexanohydroxamic acid, PA0 3R-(2,2-Dimethyl-1S-(thiazol-2-ylcarbamoyl)-propylcarbamoyl)-5-methyl-2S-pr open-2-yl-hexanohydroxamic acid, PA0 3R-(2,2-Dimethyl-1S-(thiazol-2-ylcarbamoyl)-propylcarbamoyl)-2S-hydroxy-5-m ethylhexanohydroxamic acid, and PA0 3R-(2,2-Dimethyl-1S-(4-ethoxycarbonylmethylthiazol-2-ylcarbamoyl)-propylcar bamoyl)-2S-hydroxy-5-methylhexanohydroxamic acid, PA0 N.sup.1 -2,2-Dimethyl-1S-(pyridin-2-ylcarbamoyl)-propyl!-N.sup.4 -hydroxy-2R-isobutyl-3S-methoxy-succinamide PA0 5-Methyl-3R-(2-phenyl-1S-phenylcarbamoyl-ethylcarbamoyl)-hexanohydroxamic acid, PA0 3R-(2,2-Dimethyl-1S-phenylcarbamoyl-propylcarbamoyl)-5-methylhexanohydroxam ic acid, PA0 3R-(2,2-Dimethyl-1S-pyridin-2-ylcarbamoyl-propylcarbamoyl)-5-methylhexanohy droxamic acid, PA0 3R-(2,2-Dimethyl-1S-phenylcarbamoyl-propylcarbamoyl)-2S-hydroxy-5-methylhex anohydroxamic acid, PA0 2S-Hydroxy-3R-(3-methyl-1S-napth-2-ylcarbamoyl-butylcarbamoyl)-5-methylhexa nohydroxamic acid PA0 2S-Hydroxy-3R-(3-methyl-1S-(4-methoxyphenyl)carbamoyl-butylcarbamoyl)-5-met hyl-hexanohydroxamic acid, PA0 3R-(2,2-Dimethyl-1S-(4-tertbutyl-2,6-dimethylphenyl)carbamoyl-propylcarbamo yl)-2S-hydroxy-5-methylhexanohydroxamic acid, PA0 3R-(2,2-Dimethyl-1S-(4-methoxyphenyl)carbamoyl-propylcarbamoyl)-2S-hydroxy- 5-methylhexanohydroxamic acid, PA0 3R-(2,2-Dimethyl-1S-pyrid-4-ylcarbamoyl-propylcarbamoyl)-2S-hydroxy-5-methy lhexanohydroxamic acid, PA0 3R-(2,2-Dimethyl-1S-(4-hydroxyphenyl)carbamoyl-propylcarbamoyl)-2S-hydroxy- 5-methylhexanohydroxamic acid, PA0 3R-(2-Benzylthio-2-methyl-1S-(pyridin-2-ylcarbamoyl)propylcarbamoyl)-2S-hyd roxy-5-methylhexanohydroxamic acid, PA0 3R-(2,2-Dimethyl-1S-phenylcarbamoyl-propylcarbamoyl)-2S-hydroxy-5-phenylhex anohydroxamic aci PA0 3R-(2,2-Dimethyl-1S-(4,5-dimethylthiazol-2-ylcarbamoyl)-propylcarbamoyl)-2S -hydroxy-5-methylhexanohydroxamic acid, PA0 3R-(2,2-Dimethyl-1S-(5-bromo-thiazol-2-ylcarbamoyl)-propylcarbamoyl)-2S-hyd roxy-5-methylhexanohydroxamic acid, PA0 3R-(2,2-Dimethyl-1S-(4-phenyl-thiazol-2-ylcarbamoyl)-propylcarbamoyl)-2S-hy droxy-5-methylhexanohydroxamic acid, PA0 3R-(2,2-Dimethyl-1S-(4-tert-butylthiadiazol-2-ylcarbamoyl)-propylcarbamoyl) -2S-hydroxy-5-methylhexanohydroxamic acid, PA0 3R-(2,2-Dimethyl-1S-phenylcarbamoyl-propylcarbamoyl)-5-methyl-2S-propen-2-y l-hexanohydroxamic acid, PA0 3R-(2,2-Dimethyl-1S-(4-methoxyphenylcarbamoyl)-propylcarbamoyl)-5-methyl-2S -propen-2-yl-hexanohydroxamic acid, PA0 3R-(2-Benzylthio-2-methyl-1S-(pyridin-2-ylcarbamoyl)-propylcarbamoyl)-5-met hyl-2S-propen-2-yl-hexanohydroxamic acid, PA0 3R-(2,2-Dimethyl-1S-(pyridin-3-ylcarbamoyl)-propylcarbamoyl)-5-methyl-2S-pr open-2-yl-hexanohydroxamic acid, PA0 3R-(2,2-Dimethyl-1S-(4-hydroxyphenylcarbamoyl)-propylcarbamoyl)-5-methyl-2S -propen-2-yl-hexanohydroxamic acid, PA0 3R-(2,2-Dimethyl-1S-(3-methoxyphenylcarbamoyl)-propylcarbamoyl)-5-methyl-2S -propen-2-yl-hexanohydroxamic acid, PA0 3R-(2,2-Dimethyl-1S-(pyridin-4-ylcarbamoyl)-propylcarbamoyl)-5-methyl-2S-pr open-2-yl-hexanohydroxamic acid, PA0 3R-(2,2-Dimethyl-1S-(2-methoxyphenylcarbamoyl)-propylcarbamoyl)-5-methyl-2S -thien-2-ylsulfanylmethyl-hexanohydroxamic acid, PA0 3R-(2,2-Dimethyl-1S-(pyridin-2-ylcarbamoyl)-propylcarbamoyl)-5-methyl-2S-th ien-2-ylsulfanylmethyl-hexanohydroxamic acid, PA0 3R-(2,2-Dimethyl-1S-(2-methoxyphenylcarbamoyl)-propylcarbamoyl)-5-methyl-2S -thien-2-ylsulfinylmethyl-hexanohydroxamic acid, PA0 3R-(2,2-Dimethyl-1S-(pyridin-2-ylcarbamoyl)-propylcarbamoyl)-5-methyl-2S-th ien-2-ylsulfinylmethyl-hexanohydroxamic acid, PA0 3R-(2,2-Dimethyl-1S-phenylcarbamoyl-propylcarbamoyl)-2S-hydroxy-5-phenylhex anoic acid, PA0 3R-(2,2-Dimethyl-1S-(N-oxy-pyridin-2-yl)carbamoyl-propylcarbamoyl)-2S-hydro xy-5-methylhexanohydroxamic acid, PA0 DIPE Diisopropyl ether PA0 DMF N,N-Dimethylformamide PA0 HOBt 1-Hydroxybenzotriazole PA0 LDA Lithium diisopropylamide PA0 mCPBA m-Chloroperbenzoic acid PA0 NMM N-Methylmorpholine PA0 THF Tetrahydrofuran PA0 TFA Trifluoroacetic acid PA0 TLC Thin layer chromatography PA0 EDC N-Ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride
The following patent publications disclose carboxylic acid-based MMP inhibitors: